Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound that inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus that can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces or ablates that risk.
Jones et al (U.S. Pat. No. 5,688,810) described the PR antagonist dihydroquinoline A. 
Jones et al described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones et al described compound C (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41, 291, 1998). 
Zhi et al described the ether G as a PR antagonist (J. Med. Chem. 41, 291, 1998). 
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38, 4880, 1995). 
Perlman et al described the vitamin D analog I as a PR ligand (Tetrahedron. Lett. 35, 2295, 1994). 
Hamann et al described the PR antagonist J (Ann. N.Y. Acad. Sci. 761, 383, 1995). 
Chen et al described the PR antagonist K (Chen et al, POI-37, 16th Int. Cong. Het. Chem, Montana, 1997). 
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997). 
Kuhla et al claimed the oxindole M as a cardiotonic (WO 86/03749). 
Weber claimed the oxindole N for cardiovascular indications (WO 91/06545). 
Fischer et al claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516). 
Singh et al described the PDE III inhibitor P (J. Med. Chem. 37, 248, 1994). 
Andreani et al described the cytotoxic agent Q (Acta. Pharn. Nord, 2, 407, 1990). 
Binder et al described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767). 
Walsh (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 4,670,566). 
R1=F, Cl, Br, alkyl, NH2 
R2=alkyl, alkoxy, F, Cl, NH2, CF3 
Bohm et al claim the oxindole T as cardiovascular agents (WO 91/06545). 
Bohm et al include the generic structure U (WO 91/04974). 
A Japanese patent contains the generic structure V (JP 63112584 A). 
Boar et al described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1). 
Kende et al described methodology for preparing 3,3-substituted oxindoles, e.g., X, that was utilized in the present invention (Synth. Commun. 12, 1, 1982). 
There are numerous literature reports that disclose a number of benzoxazin-2-ones. However, none of these examples in these patents contain substituents necessary for the compounds to be active as progesterone receptor modulators.
Among these publications, Narr et al (German Patent, DE 3633861, CA 109:22973) claimed that imidazobenzoxazinones, e.g. Y, as cardotonics; Benzoxazin-2-ones, such as brofoxine (Z), being active as an anxiolytic was reported by Hartmann et al (Proc. West. Pharmacol. Soc. 21, 51-55 (1978)). More recently, a number of patents (e.g., Young et al WO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such as compounds AA and BB as inhibitors of HIV reverse transcriptase. 